Inflammation is a molecular, cellular, and tissue program during which foreign substances and pathogens are destroyed, and injured tissue is repaired through a variety of biochemical, biophysical, and cellular mechanisms. The principal cellular mediators of inflammation are leukocytes. Two main classes of leukocytes that sustain the inflammatory processes are granulocytes and monocytes/macrophages. Macrophages form an important part of the mammalian host defense system in normal and pathological processes.
Macrophages are derived from a pool of monocytes that have migrated into peripheral tissues such as those of the liver, spleen, lung, lymph nodes, peritoneum, skin, brain, and bone, where they differentiate into macrophages. The major characteristic of macrophages is their ability to recognize, internalize, and destroy a variety of foreign (non-self) and endogenous substances and pathogens including bacteria, parasites, and viruses. The exact recognition mechanism for non-self pathogens is unknown, but it has been proposed that receptors with broad binding specificity are used to discriminate between self and non-self antigens. Macrophages are also thought to play an important role in the immune response by presenting foreign antigens to lymphocytes.
Signal transduction is the general process by which cells respond to extracellular signals. Extracellular signals are mediated through a biochemical cascade that begin with the binding, of a signal molecule, e.g., a hormone, neurotransmitter, or growth factor, to a cell membrane receptor and end with the activation of an intracellular target molecule. This process of signal transduction regulates all types of cell functions including cell proliferation, differentiation, and gene transcription.
GTP binding protein (G protein) signaling is one of the important biochemical pathways of signal transduction. C protein coupled receptors (GPCR) are a superfamily of integral membrane proteins which transduce extracellular signals. GPCRs include receptors for biogenic amines; for lipid mediators of inflammation, peptide hormones, and sensory signal mediators. The GPCR becomes activated when the receptor binds its extracellular ligand. Conformational chances in the GPCR which result from the ligand-receptor interaction affect the binding affinity of a G protein to the GPCR intracellular domains. This enables GTP to bind with enhanced affinity to the G protein. Activation of the G protein by GTP leads to the interaction of the G protein .alpha. subunit with adenylate cyclase or other second messenger molecule generator. This interaction regulates the activity of adenylate cyclase and hence production of a second second messenger molecule, cAMP. cAMP regulates phosphorylation and activation of other intracellular proteins. Alternatively, cellular levels of other second messenger molecules, such as, for example, cGMP or eicosinoids, may be upregulated or downregulated by the activity of GPCRs. The G protein .alpha. subunit is deactivated by hydrolysis of the GTP by GTPase and the .beta..gamma. and .alpha. subunits reassociate. The heteromeric G protein then dissociates from the adenylate cyclase or other second messenger molecule generator. Activity of GPCR may also be regulated by phosphorylation of the intra- and extracellular domains or loops.
The structure of these highly-conserved receptors consists of seven hydrophobic transmembrane (serpentine) regions, cysteine disulfide bridges between the second and third extracellular loops, an extracellular N-terminus, and a cytoplasmic C-terminus. Three extracellular loops alternate with three intracellular loops to link the seven transmembrane regions. The most conserved parts of these proteins are the transmembrane regions and the first two cytoplasmic loops. A conserved, acidic-Arg-aromatic residue triplet present in the second cytoplasmic loop may interact with the G-proteins. The consensus pattern of the G-protein coupled receptors signature (PS00237; SWISSPROT) is characteristic of most proteins belonging to this superfamily (Watson, S. and S. Arkinstall (1994) The G-protein Linked Receptor Facts Book, Academic Press, San Diego, Calif., pp 2-6).
Examples of GPCRs implicated in inflammation and the immune response include the EGF module-containing, mucin-like hormone receptor (Emr1) and CD97.beta. receptor proteins. These seven transmembrane hormone receptors exist as heterodimers in vivo and contain between three and seven potential calcium-binding EGF-like motifs (Baud, V. et al. (1995) Genomics 26:334-344; Gray, J. X. et al. (1996) J. Immunol. 157:5438-5447). In addition, an orphan Emr1-like GPCR (g2935597, NCBI GenBank) has recently been mapped to human chromosome 19. These GPCRs are members of the recently characterized EGF-TM7 receptors family.
The discovery of a new human Emr1-like G protein coupled receptor and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of respiratory, inflammatory, and immunological disorders.